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Special Issue "Hsp90 Inhibitors"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (30 May 2012)

Special Issue Editor

Guest Editor
Dr. Kip West

Section of Pharmacology, Infinity Pharmaceuticals, 780 Memorial Drive, Cambridge, MA 02139, USA
Interests: HSP90; PI3K/AKT/mTOR signaling pathway; RAS/RAF/MEK signaling pathway; EGFR/ErbB family signaling pathway(s); Cancer; Non-small cell lung cancer; colorectal cancer; pancreatic cancer

Special Issue Information

Dear Colleagues,

Cancer is a disease that has been demonstrated to involve the dysregulation of a minority of different key proteins or signaling pathways within cells which manifests itself in the aberrant expression and/or function of these proteins/pathways. Heat shock protein 90 (Hsp90) has been shown to play an integral role in regulating the stability of a number of these key cancer-causing proteins through its role as a protein chaperone. Proteins chaperoned by Hsp90, known as client proteins, include cancer-causing forms of ALK, BCR-ABL, EGFR, FLT3, and HER2. This role in controlling the activity of multiple client proteins makes Hsp90 an attractive target for therapeutic intervention. Indeed, Infinity Pharmaceuticals, as well as others, have shown the potential clinical utility of inhibiting Hsp90 function in the management of different malignancies including non-small cell lung cancer, gastro-intestinal stromal tumors and breast cancer. The purpose of this special issue is to evaluate the current status of Hsp90 inhibitors in preclinical and clinical development, review historical findings and examine where this exciting area of research and therapeutic development will lead in the future.

Dr. Kip A. West
Guest Editor

Published Papers (8 papers)

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Research

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Open AccessArticle Pertuzumab Increases 17-AAG-Induced Degradation of ErbB2, and This Effect Is Further Increased by Combining Pertuzumab with Trastuzumab
Pharmaceuticals 2012, 5(7), 674-689; doi:10.3390/ph5070674
Received: 20 April 2012 / Revised: 13 June 2012 / Accepted: 21 June 2012 / Published: 28 June 2012
Cited by 6 | PDF Full-text (620 KB) | HTML Full-text | XML Full-text
Abstract
ErbB2 is an important oncogenic protein involved in carcinogenesis of, among others, breast, gastric, and ovarian carcinoma. Over-expression of ErbB2 is found in almost 20% of breast cancers, and this results in proliferative and anti-apoptotic signalling. ErbB2 is therefore an important treatment [...] Read more.
ErbB2 is an important oncogenic protein involved in carcinogenesis of, among others, breast, gastric, and ovarian carcinoma. Over-expression of ErbB2 is found in almost 20% of breast cancers, and this results in proliferative and anti-apoptotic signalling. ErbB2 is therefore an important treatment target. Antibodies recognizing full-length ErbB2 are clinically established, and drugs targeting the ErbB2 stabilizing heat shock protein 90 (Hsp90) are under clinical evaluation. We have investigated effects of the ErbB2-binding antibodies trastuzumab and pertuzumab alone and in combination, as well as the effect of the antibodies in combination with the Hsp90 inhibitor 17-AAG. Our results confirm the notion that combination of different ErbB2-binding antibodies more efficiently down-regulates ErbB2 than does one antibody in isolation. Additionally, our data demonstrate that ErbB2 is most efficiently down-regulated upon incubation with anti-ErbB2 antibodies in combination with Hsp90 inhibitors. The combination of anti-ErbB2 antibodies, and especially the combination of antibodies with 17-AAG, did also increase the inhibition of Akt activation of either agent, which could suggest an anti-proliferative effect. In such case, combining these agents could be beneficial in treatment of tumors not responding to trastuzumab only. Full article
(This article belongs to the Special Issue Hsp90 Inhibitors)
Open AccessArticle Photodynamic Therapy with Hypericin Improved by Targeting HSP90 Associated Proteins
Pharmaceuticals 2011, 4(11), 1488-1502; doi:10.3390/ph4111488
Received: 1 September 2011 / Revised: 1 November 2011 / Accepted: 7 November 2011 / Published: 10 November 2011
Cited by 2 | PDF Full-text (322 KB) | HTML Full-text | XML Full-text
Abstract
In this study we have focused on the response of SKBR-3 cells to both single 17-DMAG treatment as well as its combination with photodynamic therapy with hypericin. Low concentrations of 17-DMAG without any effect on survival of SKBR-3 cells significantly reduced metabolic [...] Read more.
In this study we have focused on the response of SKBR-3 cells to both single 17-DMAG treatment as well as its combination with photodynamic therapy with hypericin. Low concentrations of 17-DMAG without any effect on survival of SKBR-3 cells significantly reduced metabolic activity, viability and cell number when combined with photodynamic therapy with hypericin. Moreover, IC10 concentation of 17-DMAG resulted in significant increase of SKBR-3 cells in G1 phase of the cell cycle, followed by an increase of cells in G2 phase when combined with photodynamic therapy. Furthermore, 17-DMAG already decreased HER2, Akt, P-Erk1/2 and survivin protein levels in SKBR-3 cells a short time after its application. In this regard, 17-DMAG protected also SKBR-3 cells against both P-Erk1/2 as well as survivin upregulations induced by photodynamic therapy with hypericin. Interestingly, IC10 concentration of 17-DMAG led to total depletion of Akt, P-Erk1/2 proteins and to decrease of survivin level at 48 h. On the other hand, 17-DMAG did not change HER2 relative expression in SKBR-3 cells, but caused a significant decrease of HER2 mRNA in MCF-7 cells characterized by low HER2 expression. These results show that targeting HSP90 client proteins increases the efficiency of antineoplastic effect of photodynamic therapy in vitro. Full article
(This article belongs to the Special Issue Hsp90 Inhibitors)
Open AccessArticle Degradable Cross-Linked Nanoassemblies as Drug Carriers for Heat Shock Protein 90 Inhibitor 17-N-Allylamino-17-demethoxy-geldanamycin
Pharmaceuticals 2011, 4(10), 1281-1292; doi:10.3390/ph4101281
Received: 8 August 2011 / Revised: 7 September 2011 / Accepted: 19 September 2011 / Published: 26 September 2011
Cited by 4 | PDF Full-text (610 KB) | HTML Full-text | XML Full-text
Abstract
Cross-linked nanoassemblies (CNAs) with a degradable core were prepared for sustained release of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), a potent inhibitor of heat shock protein 90 (HSP90). The particle size of CNAs ranged between 100 and 250 nm, which changed depending on the cross-linking yields [...] Read more.
Cross-linked nanoassemblies (CNAs) with a degradable core were prepared for sustained release of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), a potent inhibitor of heat shock protein 90 (HSP90). The particle size of CNAs ranged between 100 and 250 nm, which changed depending on the cross-linking yields and drug entrapment method. CNAs with a 1% cross-linking yield entrapped 17-AAG in aqueous solutions, yet degraded in 3 hrs. CNAs entrapped 5.2 weight% of 17-AAG as the cross-linking yield increased to 10%, retaining more than 80% of particles for 24 hrs. CNAs with drugs entrapped after the cross-linking reactions were 100 nm and remained stable in both pH 7.4 and 5.0, corresponding to the physiological, tumoral, and intracellular environments. Drug was completely released from CNAs in 48 hrs, which would potentially maximize drug delivery and release efficiency within tumor tissues. Drug release patterns were not negatively affected by changing the cross-linking yields of CNAs. CNAs entrapping 17-AAG suppressed the growth of human non-small cell lung cancer A549 cells as equally effective as free drugs. The results demonstrated that CNAs would be a promising formulation that can be used in aqueous solutions for controlled delivery and release of 17-AAG. Full article
(This article belongs to the Special Issue Hsp90 Inhibitors)
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Review

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Open AccessReview Heat Shock Protein 90 (Hsp90) Expression and Breast Cancer
Pharmaceuticals 2012, 5(9), 1008-1020; doi:10.3390/ph5091008
Received: 19 July 2012 / Revised: 30 August 2012 / Accepted: 10 September 2012 / Published: 12 September 2012
Cited by 7 | PDF Full-text (190 KB) | HTML Full-text | XML Full-text
Abstract
Hsp90 is an abundant protein in mammalian cells. It forms several discrete complexes, each containing distinct groups of co-chaperones that assist protein folding and refolding during stress, protein transport and degradation. It interacts with a variety of proteins that play key roles [...] Read more.
Hsp90 is an abundant protein in mammalian cells. It forms several discrete complexes, each containing distinct groups of co-chaperones that assist protein folding and refolding during stress, protein transport and degradation. It interacts with a variety of proteins that play key roles in breast neoplasia including estrogen receptors, tumor suppressor p53 protein, angiogenesis transcription factor HIF-1alpha, antiapoptotic kinase Akt, Raf-1 MAP kinase and a variety of receptor tyrosine kinases of the erbB family. Elevated Hsp90 expression has been documented in breast ductal carcinomas contributing to the proliferative activity of breast cancer cells; whilst a significantly decreased Hsp90 expression has been shown in infiltrative lobular carcinomas and lobular neoplasia. Hsp90 overexpression has been proposed as a component of a mechanism through which breast cancer cells become resistant to various stress stimuli. Therefore, pharmacological inhibition of HSPs can provide therapeutic opportunities in the field of cancer treatment. 17-allylamino,17-demethoxygeldanamycin is the first Hsp90 inhibitor that has clinically been investigated in phase II trial, yielding promising results in patients with HER2-overexpressing metastatic breast cancer, whilst other Hsp90 inhibitors (retaspimycin HCL, NVP-AUY922, NVP-BEP800, CNF2024/BIIB021, SNX-5422, STA-9090, etc.) are currently under evaluation. Full article
(This article belongs to the Special Issue Hsp90 Inhibitors)
Open AccessReview Molecular Dynamics Simulations of Hsp90 with an Eye to Inhibitor Design
Pharmaceuticals 2012, 5(9), 944-962; doi:10.3390/ph5090944
Received: 5 July 2012 / Revised: 28 August 2012 / Accepted: 31 August 2012 / Published: 10 September 2012
Cited by 1 | PDF Full-text (903 KB) | HTML Full-text | XML Full-text
Abstract
Proteins carry out their functions through interactions with different partners. Dynamic conformational switching among different structural sub-states favors the adaptation to the shapes of the different partners. Such conformational changes can be determined by diverse biochemical factors, such as ligand-binding. Atomic level [...] Read more.
Proteins carry out their functions through interactions with different partners. Dynamic conformational switching among different structural sub-states favors the adaptation to the shapes of the different partners. Such conformational changes can be determined by diverse biochemical factors, such as ligand-binding. Atomic level investigations of the mechanisms that underlie functional dynamics may provide new opportunities for the discovery of leads that target disease-related proteins. In this review, we report our views and approaches on the development of novel and accurate physical-chemistry-based models for the characterization of the salient aspects of the ligand-regulated dynamics of Hsp90, and on the exploitation of such new knowledge for the rational discovery of inhibitors of the chaperone. Full article
(This article belongs to the Special Issue Hsp90 Inhibitors)
Open AccessReview Hsp90 Inhibitors and the Reduction of Anti-Cancer Drug Resistance by Non-Genetic and Genetic Mechanisms
Pharmaceuticals 2012, 5(9), 890-898; doi:10.3390/ph5090890
Received: 6 July 2012 / Revised: 20 August 2012 / Accepted: 24 August 2012 / Published: 30 August 2012
Cited by 3 | PDF Full-text (235 KB) | HTML Full-text | XML Full-text
Abstract
In this review, we focus on how inhibitors of Hsp90 can help prevent the resistance to anti-cancer drugs by synergistically increasing their cancer killing abilities and thereby allowing them to function at much lower concentrations than normally used. Hsp90 helps to fold [...] Read more.
In this review, we focus on how inhibitors of Hsp90 can help prevent the resistance to anti-cancer drugs by synergistically increasing their cancer killing abilities and thereby allowing them to function at much lower concentrations than normally used. Hsp90 helps to fold numerous client proteins, such as Akt, Raf, Src, chromatin-modifying proteins, nuclear hormone receptors, and kinetochore assembly proteins. We discuss four mechanisms by which Hsp90 inhibitors can potentially synergize with anti-cancer drugs: by making a drug-resistant protein that is a client for Hsp90 more sensitive to the drug, by increasing chromosomal aneuploidy and the effectiveness of DNA-damaging drugs, by inhibiting Trithorax proteins which trimethylate histone 3 at lysine 4 (H3K4me3) and thereby decreasing expression of tumor promoter genes, and by interacting with the negative elongation factor (NELF) complex in tumors. We also explain how the evolutionary capacitor function of Hsp90 can be exploited with inhibitors of Hsp90 by exposing new protein variants that can be targeted with other drugs, thereby opening new avenues of combination drug therapy to treat cancer. We believe that inhibition of these processes can increase the efficacy of Hsp90 inhibitors with other anti-cancer drugs. Full article
(This article belongs to the Special Issue Hsp90 Inhibitors)
Open AccessReview Heat Shock Protein 90 and Role of Its Chemical Inhibitors in Treatment of Hematologic Malignancies
Pharmaceuticals 2012, 5(8), 779-801; doi:10.3390/ph5080779
Received: 4 June 2012 / Revised: 9 July 2012 / Accepted: 16 July 2012 / Published: 25 July 2012
Cited by 4 | PDF Full-text (317 KB) | HTML Full-text | XML Full-text
Abstract
Heat shock protein 90 (Hsp90) is a conserved and constitutively expressed molecular chaperone and it has been shown to stabilize oncoproteins and facilitate cancer development. Hsp90 has been considered as a therapeutic target for cancers and three classes of Hsp90 inhibitors have [...] Read more.
Heat shock protein 90 (Hsp90) is a conserved and constitutively expressed molecular chaperone and it has been shown to stabilize oncoproteins and facilitate cancer development. Hsp90 has been considered as a therapeutic target for cancers and three classes of Hsp90 inhibitors have been developed: (1) benzoquinone ansamycin and its derivatives, (2) radicicol and its derivates, and (3) small synthetic inhibitors. The roles of these inhibitors in cancer treatment have been studied in laboratories and clinical trials, and some encouraging results have been obtained. Interestingly, targeting of Hsp90 has been shown to be effective in inhibition of cancer stem cells responsible for leukemia initiation and progression, providing a strategy for finding a cure. Because cancer stem cells are well defined in some human leukemias, we will focus on hematologic malignancies in this review. Full article
(This article belongs to the Special Issue Hsp90 Inhibitors)
Open AccessReview Mechanisms of Resistance to Hsp90 Inhibitor Drugs: A Complex Mosaic Emerges
Pharmaceuticals 2011, 4(11), 1400-1422; doi:10.3390/ph4111400
Received: 31 August 2011 / Revised: 4 October 2011 / Accepted: 17 October 2011 / Published: 25 October 2011
Cited by 15 | PDF Full-text (384 KB) | HTML Full-text | XML Full-text
Abstract
The molecular chaperone Hsp90 holds great promise as a cancer drug target, despite some of the initial clinical trials of Hsp90 inhibitor drugs having not lived up to expectation. Effective use of these drugs will benefit greatly from a much more detailed [...] Read more.
The molecular chaperone Hsp90 holds great promise as a cancer drug target, despite some of the initial clinical trials of Hsp90 inhibitor drugs having not lived up to expectation. Effective use of these drugs will benefit greatly from a much more detailed understanding of the factors that contribute to resistance, whether intrinsic or acquired. We review how cell culture studies have revealed a number of different mechanisms whereby cells can be rendered less susceptible to the effects of Hsp90 inhibitor treatment. A major influence is Hsp90 inhibition causing strong induction of the heat shock response, a stress response that increases cellular levels of prosurvival chaperones such as Hsp27 and Hsp70. Another problem seems to be that these inhibitors do not always access the Hsp90 proteins of the mitochondrion, forms of Hsp90 that—in cancer cells—are operating to suppress apoptosis. It should be possible to overcome these drawbacks through the appropriate drug redesign or with the combinatorial use of an Hsp90 inhibitor with a drug that targets either heat shock factor or the chaperone Hsp70. Still though, cells will often differ in the key antiapoptotic versus proapoptotic activities that are dependent on Hsp90, in the key steps in their apoptotic pathways responsive to Hsp90 inhibition or Hsp70 level, as well as the extents to which their survival is dependent on oncogenic tyrosine kinases that are clients of Hsp90. A systems approach will therefore often be required in order to establish the most prominent effects of Hsp90 inhibition in each type of cancer cell. Full article
(This article belongs to the Special Issue Hsp90 Inhibitors)

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